Topical administration of therapeutic agents to mucosal tissues is desirable for several reasons. Mucosal delivery is generally non-invasive, thereby avoiding uncomfortable aspects of intravenous, intramuscular, or subcutaneous delivery that can reduce patient compliance. Topical administration to mucosal tissue can reduce the effect of first-pass metabolism and clearance by circulating immune cells, meaning that more drug reaches the target before being metabolized. Topical administration can also produce a predominantly localized effect thereby minimizing side effects associated with systemic drug circulation. However, given the tendency of natural fluids and secretions to clear the drug from the site of administration, topical administration to mucosal sites, such as the eye, nose and mouth, can be challenging.
Topical administration is the most common delivery method employed for treating diseases and conditions affecting the eye, such as dry eye syndrome (DES). DES is defined as a multifactorial disease affecting the tear film and the ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface. DES is also accompanied by increased osmolality of the tear film and inflammation of the ocular surface. Over 30 million people in the U.S. exhibit dry eye syndrome (DES). Of these, 4.8 million have moderate to severe DES and use Restasis® (Allergan Inc., Irvine, Calif.), an ophthalmic emulsion comprising 0.05% wt/vol cyclosporine A (CsA, an immunosuppressant). Restasis® is the first commercially-available eye drop formulation that showed an increase in natural tear production in dry eye patients, in part by acting to reduce inflammation and concurrent loss of the conjunctival epithelium and goblet cells.
Eye drops, such as Restasis®, are the most popular method of delivering therapeutics to the eye due to their convenience and non-invasiveness. However, their biggest challenge is rapid clearance due to tear dilution and turnover: more than 95% of the administered drugs are cleared before they reach their intended target. Hence, eye drop formulations often must be administered frequently (twice daily for Restasis®, but up to four times for many topical drugs) and at high doses so that the drug concentrations may reach the therapeutic window. The requirement for frequent dosing reduces patient compliance. Furthermore, the high overall dosage of the administered drugs results in increased side effects: approximately 25% of people in a phase III safety evaluation of Restasis® reported experiencing one or more adverse effects such as burning, stinging and foreign body sensation on the ocular surface (Sall et al. 2000; Barber et al., 2005). Since DES requires constant long-term treatment of its symptoms, reducing the dosage of CsA using a more efficient drug delivery platform is desired and may likely reduce side effects and improve patient compliance, without compromising therapeutic efficacy. In addition, lower administration rates would reduce the likelihood for adverse reactions to the preservatives that are commonly included in topical formulations and which are a common cause of ocular surface damage.
Nanoparticles (NP) as drug carriers have been proposed to address the challenges associated with conventional eye drop delivery methods. By encapsulating drugs as their cargo, NPs may increase the concentration of drugs in the formulation, control the release rates of the drugs, and improve corneal retention by targeting the ocular surface. The controlled release of drugs from the NP drug carriers may also reduce the total amount of drug exposed on the ocular tissue at any given time, thus reducing the risk of side effects. Moreover, the small size of the NP (particle sizes 10 μm) eliminates discomfort experienced by users from administration of larger particles. Certain NP formulations may also be tuned to achieve transparency and viscosity similar to that of water. A number of polyester based polymers, such as poly(lactic-co-glycolic acid) (PLGA), poly(glycolic acid) (PGA), poly(ε-caprolactone) (PCL), and poly(lactic acid) (PLA) have been explored as suitable materials for preparing a NP drug delivery platform for targeting eye diseases. These NPs have been coated with polyethylene glycol (PEG) to improve their colloidal stability.
Recently, the present inventors developed an amphiphilic block copolymer composed of poly(D,L-lactic acid) and dextran (PLA-b-Dex) to formulate NP drug carriers (Verma et al., 2012). US 2014/0005379, entitled “Nanoparticle delivery system and components thereof”, describes nanoparticles formed from amphiphilic block copolymers comprising polylactide and dextran as drug delivery system. Dextran is conjugated to a targeting moiety in a manner that the surface of the nanoparticle is coated with the targeting moiety. The size and the targeting of the nanoparticles can be tuned by controlling the surface density of the targeting moiety.
Dextran provides a unique advantage over PEG-based materials due to its greater hydrophilicity and significantly higher density of functional groups for surface modification. Furthermore, dextran based NPs have previously demonstrated superior colloidal stability compared to PEG based NPs. Dextran has three hydroxyl groups per monomer, whereas PEG only has one functional end group per chain: increased functional groups improves the efficiency of surface modification and consequently provides greater control over the surface properties of the NPs. Previously, the present inventors modified the surface of PLA-b-Dex NPs with phenylboronic acid (PBA) molecules to achieve mucoadhesion through covalent linkage between PBA and the cis-diol groups of carbohydrates abundant on the ocular mucous membrane (Liu et al. 2012). By covalent attachment, PBA-modified NPs provide a greater affinity towards mucous membranes compared to the more commonly studied mucous-targeting molecules, such as chitosan, which rely on physical interaction with the mucous membrane.
Since the NPs target the surface mucous membrane, the rate of clearance of the NPs is likely reflected by the turnover rate of the ocular mucous membrane. The present inventors previously demonstrated significantly improved mucoadhesive properties using PBA-modified NPs, compared to Chitosan-based or thiol-based NPs, and a sustained release of CsA for up to 5 days. It was further demonstrated that the CsA-loaded NPs were biocompatible on rabbit eyes, and were effective in treating dry eye conditions in a short term study on mice (Liu et al. 2014). The effects of chronic treatment in a dry eye model were not examined.
It is desirable to provide improved compositions and methods for topical administration of therapeutic agents to mucosal tissues.